What are the earliest events and what are the factors with greatest impact in the pathogenesis of CKD-MBD?
58 Comments
Muhammad Soobadar
the earliest event is
decreased klotho and increased FGF23
Decrease 1& hydroxylase and decrease vitamin d activation and decrease ca
PTH increased as result CaSR/VDR
Factors with greatest impact
1/rate of decline of kidney function
2/ Inadequate control of phosphate
3/ use of calcium binders in patient with low turnover bone disease or previous vascular calcification
4 PTH level above 398 due to inadequate vitamin D level / or inceased phosphate
Theearliestevents:
* reduced renalmass, klotho deficiency, increased FGF23 (inhibit NaPi2a,c in PCT and NaPi2b in intestine reducing both phosphorus absorbtion & reabsorbtion # inhibit 1alpha hydroxylase reducing vitamin D activation, hence calcium and phosphorus absorbtion # inhibit PTH secretion) * VitaminD deficiency & hypo–calcemia & hyperphosphatemia causes SHPT whichaffectsboneremodeling that promote bone restoration and inhibit bone formation unless unjustifieduseofcalciumandactivevitaminDsupplements.
Factors with great impact on the pathogenesis: * aging of CKD population, increase incidence of DM as a cause of CKD, excess calcium and vitaminD analogies hanged pattern of bone lesions from high to low turn over bone disease
The earliest events are increase in FGF23 and reduction of klotho, FGF23 decreases phosphate excretion and in the renal tubule and decreases intestinal phosphate absorption and decreases 125(OH)2d3 . the increase of FGF23 conducted increase of PTH. the increase of PTH and FGF23 the two main hormones involving the regulation of renal phosphate handling. The factors greatest impact in the pathogenesis the excessive use of active vitamin d and calcium diabetic nephropathy
The earliest events are the decrease in Klotho, increase in FGF 23, and the reduction of renal mass.
at early stages, FGF inhibits the alpha-hydroxylase activity decreasing calcitriol synthesis.
Both decreased Clcitriol and increase FGF 23 lead to increased PTH and increase phosphorus excretion. The factors of great impact are the unjustified use of active vit D receptor activators and calcium causing excessive suppression of PTH and reduction of bone remodeling.
The earliest events in the pathogenesis of CKD-MBD?
It is currently accepted that increase in FGF23, the decrease of Klotho, and the reduction of renal mass are possibly the earliest events in the pathogenesis of CKD-MBD. These changes favor the reduction of 1-α-hydroxylase in the kidney, which results in low levels of calcitriol, the most active natural activator of VDR, a fact that reduces the absorption of calcium in the intestine and favors the decrease in serum calcium, which in turn acts as a stimulus for the synthesis and release of PTH. The increase in PTH favors bone turnover and resorption and stimulates the production of 1-α-hydroxylase. All of these mechanisms translate into compensatory increases to normalize serum calcium. Furthermore, the increase in FGF23 and PTH favor urinary phosphate excretion, maintaining normal serum phosphate levels until stages 3–4 of CKD .Despite the compensatory increases in PTH, it is well known that in CKD there is currently a hyporesponsiveness to PTH which limits its action .
The factors with greatest impact in the pathogenesis of CKD-MBD?
As consequence of the inappropriate or excessive use of some therapies, CKD-MBD can also be facilitated and/or aggravated. Two factors with great negative repercussions are, the excessive use of calcium and vitamin D receptor activators (VDRAs), which through inadequate increases in serum calcium can favor the excessive suppression of PTH and the reduction of bone remodeling .
aging and DM also contribute to the development of CKD-MBD.
The earliest event occurs elevation of fgf23 and decrease level of klotho level after that decrease kideny tissue so decrease vit d activation decrease absorption of ca and start stimulation of pth secrearion.
The factors with the greatest impact in pathogenesis excess use of ca supplement and vit d ageing in most of patient and immobilty
The reduction of renal mass with increase in FGF23, the decrease of Klotho, are possibly the earliest events in the pathogenesis of CKD-MBD.
Decreasing 1-α-hydroxylase in the kidney, which results in low levels of calcitriol, the mostactive natural activator of VDR ,so reduces the absorption of calcium and decrease in serum calcium, that acts as a stimulus for the synthesis and release of PTH. The increase in PTH favors bone turnover and resorption and stimulates the production of 1-α-hydroxylase, which increases and normalize serum calcium. On the other hand , the increase in FGF23 and PTH favor urinary phosphate excretion, maintaining normal serum phosphate levels until stages 3–4 of CKD. Despite the compensatory increases in PTH, but in CKD there is currently a hyporesponsiveness to PTH which limits its action. And despite the fact that FGF23 and PTH have synergistic effects in relation to the renal excretion of phosphate, but they have opposite effects on calcitriol synthesis
the factors with greatest impact in the pathogenesis of CKD-MBD?what we should expect in CKD 5 would be a high prevalence of secondary hyperparathyroidism with high bone turnover, but the latter is not the most frequent findings within the CKD-MBD in the decades the more frequent pattern of bone lesions has changed from high to low bone turnover .
Could be due to: aging of the CKD ptient, the increase in the prevalence of diabetic nephropathy, the excess of calcium and vitamin D, and the aluminum load (less frequnt now),
the earliest events in pathogenesis of CKD-MBD
1-RELEASE OF FGF23 /KLOTHO >>as phosphaturic hormones and maintain serum po4 in normal value ,and inhibit alfa 1 hydroxylase so reduce 1,25(OH)2 D3
2- by loss of nephron mass and decrease klotho >>FGF23 lost his action and increase as amarker of cardiovascular morbidity and mortality (LVH )
3-hyperphosphatemia (dt loss of action of FGF23 and increase dietary intake )
4-decrease active vitamin D dt loss of 1 alfa hydroxylation from kidney
5- mild hypocalemia dt vitamin d deficiency and hyperphosphatemia
6-elevated hyperparathyroidism
===================
at the end we have
1-increase FGF23 and decrease klotho 2-increase serum phosphate 3- hypocalcemia 4-decrease active vitamin D 5-increased PTH
the earliest event in pathogenesis in CKD -MBD
with progression of kidney function in CKD
the earliest event dysregulation of bone and mineral metabolism
hyper phosphoremia
CA
vit-D
PTH
but currently factor impact in pathogenesis of ckd-mbd
FGF-23 increased in early stage of ckd
and decrease of klotho
also another recent factor as wnt inhibitor ( sclerostin and dkk1 ) and actR11A
impact in renal bone disorders and calcification
· The earliest events of pathogenesis of CKD-MBD are:
Increase in FGF23
Decrease of Klotho
Reduction of renal mass
These changes favor the low levels of calcitriol due to reduction of 1-α-hydroxylase in the kidney. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium. Hypocalcemia leads to stimulation of the synthesis and release of PTH.
· The factors with greatest impact in the pathogenesis of CKD-MBD are:
The excessive use of calcium and vitamin D receptor activators.
The pathophysiology of CKD-MBD is complex and involves feedback loops between the kidney, the parathyroid glands, the bone, the intestine, and the vasculature; to maintain calcium and phosphorus balance.
The earliest events in the pathophysiology of CKD-MBD as a consequence of decreased renal mass include:
Loss of klotho.
Increased FGF23 secretion.
Decreased bone formation rates.
Factors with a significant impact on the pathogenesis of CKD-MBD and pattern of bone lesions:
What are the earliest events?
-Reduced renal mass and GFR
-Decrease Klotho Increase FGF23 ( mostly the first thing to happen) increase sclerostin
-What are the factors with greatest impact in the pathogenesis of CKD-MBD?
Excessive use of: 1) calcium 2)(VDRAs)/ 4) aging 5) AL load 6)immobility 7) comorbidities like DM.
the earliest events in the pathogenesis of CKD-MBD?with CKD, there is a gradual progressive decrease in the number of functioning nephrons leading to the following :
gradual decrease in phosphate excretion leading to phosphate retention leading to excess FGF-23
gradual decrease in klotho expression will lead also to phosphate retention.
gradual decrease in activation of Vit. D due to decreased activity of alpha 1-hydroxylase in renal tubules. this will lead to decreased intestinal calcium absorption leading to hypocalcemia.
hypocalcemia, hyperphosphatemia and increased FGF-23 all will lead to increase in PTH
the factors with greatest impact in the pathogenesis of CKD-MBD?
old age as CKD is more affecting elderly patients.
As CKD develops, in earlier stages, with a decrease in renal mass, klotho decreases, and an increase in FGF-23 begins. At early stages, there is an attempt to decrease phosphorus, so FGF-23 and later PTH increase, maintaining normal P level. flowing the inactivation of 1 alfa hydroxylase leads to a decrease in 1,25(OH) Vit.D later leading to hypocalcemia, an inability to maintain normal P level
Q1
In CKD diseases, the main alterations occur in Ca, phosphate, FGF23, klotho and the bit d hormonal system, including calcitriol and calcidiol, which lead to important changes in bone and vascular metabolism with very negative clinical consequences such as decreased bone mass and increased fragility, increased vascular calcifications. This process for the last six decades known as renal osteodystrophy. In 2006,a KDIGO consensus coined the new term CKD-MBD AND this is because it doesn’t confine to bone and laboratory finding alone but also other common complications.
CKD-MBD started early in CKD but became more florid in the late stages of CKD 4.5, and one of the factors that aggravate and increase the CKD-MBD is the use of excessive Ca and Vitamin D receptors activators, which can start the reduction in bone remodeling early.
It is currently accepted that an increase in FGF23, and decrease in KLOTHO, and a reduction of renal mass are the earliest events, these changes lead to a reduction in 1alpha hydroxylates which is the most natural activator of VDR., This in turn will reduce Ca absorption from the intestine, and this will lead to increase PTH production.
One of the crucial points in CKD-MBD, despite the synergistic effect of FGF23 and PTH in decreasing the phosphate level through the kidney, they have opposite effects on calcitriol synthesis, FGF23 inhibits1alpha hydroxylation, while PTH increases it.
Q2
As CKD progressed we expect to have secondary HPTH along with high bone turn over and this is not happened due to the following factors:
Ageing of ckd
DM
The excess use of Ca and Vit D, and because of this KDIGO guideline is to avoid hypercalcaemia in early CKD stage 2,3.
The earliest events in the Pathogenesis of CKD-MBD:
– An increase in FGF23,
– A decrease in Klotho,
– A decrease in renal mass
– Increased vascular and valvular calcification.
The most significant changes occur in the calcium, phosphate, PTH, FGF23/Klotho, and vitamin D hormonal systems (calcidiol and calcitriol) , which cause significant alterations in bone and vascular metabolism with severe clinical effects such as decreased bone mass, increased fragility fractures, and increased vascular and valvular calcification.
Factors with greatest impact on in the pathogenesis of CKD-MBD:
– Excessive usage of calcium and vitamin D
– Aluminum load, which is becoming less common
– Rise in the incidence of diabetes as a cause of CKD
– Aging of the CKD population
1- icreased FGF-23 levels
2- decreased klotho levels and reduced renal mass
3- inactivation of 1-alpha hydroxylase in kidney
4- decreased active form of vit D
5- hyporesponsiveness to PTH action and secondary hyperparathyroidism
6- hypocalcemia due to decreased active vit D and decreased ca absorption from the intestine
7- phosphate retention later on
The earliest events of pathogenesis of CKD-MBD are:
Increase in FGF23
Decrease of Klotho
Reduction of renal mass
These changes favor the low levels of calcitriol due to reduction of 1-α-hydroxylase in the kidney. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium. Hypocalcemia leads to stimulation of the synthesis and release of PTH.
The factors with greatest impact in the pathogenesis of CKD-MBD are:
The excessive use of calcium and vitamin D receptor activators.
the earliest change in CKD-MBD is reduction of the functioning neprons and 2 opposite hormonal responses( increase FGF-23 AND decrease klotho), accumulating into decrease hydroxylase activity,decreasing calcitrol production, thereby decreasing intestinal calcium absorption, producing hypocalciumia which in turn stimulate PTH production. 2ry hyperparathyroidism and vit D deficiency lead CKD-MBD
Increase FGF23, klotho deficiency both in parallel with reduction of renal mass are earliest changes in CKD-MBD which lead to decrease alfa hydroxylase in kidney then subsequently decrease calcitriol level which lead to decrease calcium absorption and hypocalcemia and secondary hyperparathyroidism. the pathophysiology of secondary hyperparathyroidism:1- Plasma FGF23 increase with progression of CKD stages which occur before observed changes in the levels of phosphate and PTH, (FGF23) derived from osteocytes requires klotho (a transmembrane protein) to enable it to bind to the FGF receptor (FGFR) in classic target organs such as kidneys and parathyroid glands.2- Plasma FGF23 enhances phosphate excretion in the proximal renal tubule by decreasing the expression of luminal sodium-dependent phosphate transporters and may also decrease intestinal phosphate absorption by inhibiting NaPi cotransporter activity. 3- FGF23 reduces the synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D3] by down-regulating the activity of 1α-hydroxylase In the early stages of CKD, high levels of FGF23 attenuate hyperphosphatemia at the expense of 1,25(OH)2 vitamin D suppression, thus initiating the development of secondary hyperparathyroidism.4- The decrease in serum 1,25(OH)2D3 leads to decreased intestinal calcium absorption. The triad of calcium, calcitriol and hyperphosphatemia further enhances excessive PTH secretion. 5- This excess PTH leads to mobilization of calcium from the bone and osteitis fibrosa. Other consequences of progressive worsening of kidney function include hypo-responsiveness of the vitamin D receptor (VDR) on the parathyroid gland with further enhancement of production of PTH and reduced expression of the calcium-sensing receptor on the parathyroid gland leading to parathyroid gland hyperplasia. In some subsets of patients, the parathyroid gland undergoes hypertrophy and becomes autonomous
Earliest events in the pathogenesis of CKD-MBD:
1-increase in FGF23
2-decrease of klotho expression
3-reduction of renal mass
These changes lead to reduction of 1-alpha hydroxylase, decrease in calcitriol, decrease intestinal calcium absorption,hypocalcemia and secondary hyperparathyroidism
Factors with greatest impact in the pathogenesis of CKD-MBD:
Aging of the CKD population
Increase in the prevalence of diabetes as a cause of CKD
The main changes that occur in chronic kidney disease (CKD) are in calcium, phosphate, PTH, FGF23/Klotho, and the vitamin D hormonal system (calcidiol and calcitriol). These changes lead to important changes in bone and vascular metabolism, which have very negative clinical consequences, such as a decrease in bone mass, an increase in fragility fractures, and an increase in vascular and valvular calcification.
The etiology of CKD-MBD may begin with an increase in FGF23, a decrease in Klotho, and a loss in renal mass. These modifications limit kidney 1-α-hydroxylase, which lowers calcitriol, the most potent natural activator of VDR, which decreases intestinal calcium absorption and serum calcium, which stimulates PTH production and release. PTH increases bone resorption and 1-α-hydroxylase production.
The earliest events of pathogenesis of CKD-MBD are:
Increase in FGF23
Decrease of Klotho
Reduction of renal mass
These changes favor the low levels of calcitriol due to reduction of 1-α-hydroxylase in the kidney. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium. Hypocalcemia leads to stimulation of the synthesis and release of PTH.
The factors with greatest impact in the pathogenesis of CKD-MBD are:
The excessive use of calcium and vitamin D receptor activators.
-The earliest event in CKD are:
1. Increased FGF23
2. Decrease in klotho
3. Decrease in renal mass
FGF inhibit 1alpha hydroxylase, so we will have a low 1,25 OH Vit D level too. Low vitamin D will cause hypocalcemia.
The hypocalcemia will stimulate or lead to increased PTH later on. (High phosphat will lead also to increased PTH)
The effects of phosphat on PTH is also carried out through it action on caSR.
-the factors with greatest impact in the pathogenesis of CKD-MBD are:
1.increased age 2. DM 3. Excess of calcium and vitamin D use 4. Aluminum load
The earliest event in ckd – MBD are increase in FGF23, decrease in klotho and decrease in renal mass. These will lead to decrease 1 alfa hydrxylase then decrease calcitriol, calcium and at the beginning increase phosphote in urine then subsequently increase S. Phosphorous.
The factors with the greatest impact are *excessive use of calcium and vitamin D receptors activators
*inadequate increase in S. Calcium
*aging of ckd population
*increase in prevalence of DM
*aluminum load (less frequent now)
The earliest events in the Pathogenesis of CKD-MBD:
Increase in FGF23.
Decrease of Klotho.
Reduction in renal mass.
This is followed by altreation in Calcium, phosphate, PTH, and vitamin D hormonal system, (calidol and calcitriol), which lead to an important changes in bone and vascular metabolism with subsequent negative clinical sequelle:
Reduce bone mass.
Incraese bone fragility and fracture.
Incraesed vascular and valvular calcification.
Factors with greatest impact on in the pathogenesis of CKD-MBD:
Excessive use of calcium and vitamin D receptors activators.
Inadequate increase in serum calcium.
All can lead to excessive impression of PTH and the reduction of bone remodeling.
the earliest event is
decreased klotho and increased FGF23
Decrease 1& hydroxylase and decrease vitamin d activation and decrease ca
PTH increased as result CaSR/VDR
Factors with greatest impact
1/rate of decline of kidney function
2/ Inadequate control of phosphate
3/ use of calcium binders in patient with low turnover bone disease or previous vascular calcification
4 PTH level above 398 due to inadequate vitamin D level / or inceased phosphate
Low Klotho-> high FGF23-> low vit D3-> low Ca-> High PTH
Natural aging, DM, and either low or excessive Ca, Vit D would impact the pathogenesis of CKD-MBD
Great Dr. Asmaa
The earliest events:
* reduced renal mass, klotho deficiency, increased FGF23 (inhibit NaPi2a,c in PCT and NaPi2b in intestine reducing both phosphorus absorbtion & reabsorbtion # inhibit 1alpha hydroxylase reducing vitamin D activation, hence calcium and phosphorus absorbtion # inhibit PTH secretion)
* Vitamin D deficiency & hypo–calcemia & hyperphosphatemia causes SHPT which affects bone remodeling that promote bone restoration and inhibit bone formation unless unjustified use of calcium and active vitamin D supplements.
Factors with great impact on the pathogenesis:
* aging of CKD population, increase incidence of DM as a cause of CKD, excess calcium and vitamin D analogies hanged pattern of bone lesions from high to low turn over bone disease
Great job. Thanks Dr. Marwa
The earliest events are increase in FGF23 and reduction of klotho, FGF23 decreases phosphate excretion and in the renal tubule and decreases intestinal phosphate absorption and decreases 125(OH)2d3 . the increase of FGF23 conducted increase of PTH. the increase of PTH and FGF23 the two main hormones involving the regulation of renal phosphate handling.
The factors greatest impact in the pathogenesis
the excessive use of active vitamin d and calcium
diabetic nephropathy
Great Dr. Mohamed
The earliest events are the decrease in Klotho, increase in FGF 23, and the reduction of renal mass.
at early stages, FGF inhibits the alpha-hydroxylase activity decreasing calcitriol synthesis.
Both decreased Clcitriol and increase FGF 23 lead to increased PTH and increase phosphorus excretion.
The factors of great impact are the unjustified use of active vit D receptor activators and calcium causing excessive suppression of PTH and reduction of bone remodeling.
Great answer Dr. Radwa
The earliest events in the pathogenesis of CKD-MBD?
It is currently accepted that increase in FGF23, the decrease of Klotho, and the reduction of renal mass are possibly the earliest events in the pathogenesis of CKD-MBD. These changes favor the reduction of 1-α-hydroxylase in the kidney, which results in low levels of calcitriol, the most active natural activator of VDR, a fact that reduces the absorption of calcium in the intestine and favors the decrease in serum calcium, which in turn acts as a stimulus for the synthesis and release of PTH. The increase in PTH favors bone turnover and resorption and stimulates the production of 1-α-hydroxylase. All of these mechanisms translate into compensatory increases to normalize serum calcium. Furthermore, the increase in FGF23 and PTH favor urinary phosphate excretion, maintaining normal serum phosphate levels until stages 3–4 of CKD .Despite the compensatory increases in PTH, it is well known that in CKD there is currently a hyporesponsiveness to PTH which limits its action .
The factors with greatest impact in the pathogenesis of CKD-MBD?
As consequence of the inappropriate or excessive use of some therapies, CKD-MBD can also be facilitated and/or aggravated. Two factors with great negative repercussions are, the excessive use of calcium and vitamin D receptor activators (VDRAs), which through inadequate increases in serum calcium can favor the excessive suppression of PTH and the reduction of bone remodeling .
aging and DM also contribute to the development of CKD-MBD.
Great answer Dr. Asmaa
Earliest Events
*increase in FGF32 (?secondary to initial phosphate retention)
*Decrease in Klotho
*Increase in PTH
Factors with Impacts on Pathogenesis
*Excessive use of active vitamin D
*DM prevalence
*Aging population
*Aluminum based PO4 binders
Good job. Thanks Dr. Hassan
The earliest event occurs elevation of fgf23 and decrease level of klotho level after that decrease kideny tissue so decrease vit d activation decrease absorption of ca and start stimulation of pth secrearion.
The factors with the greatest impact in pathogenesis excess use of ca supplement and vit d ageing in most of patient and immobilty
Great Dr. Rabab
The reduction of renal mass with increase in FGF23, the decrease of Klotho, are possibly the earliest events in the pathogenesis of CKD-MBD.
Decreasing 1-α-hydroxylase in the kidney, which results in low levels of calcitriol, the mostactive natural activator of VDR ,so reduces the absorption of calcium and decrease in serum calcium, that acts as a stimulus for the synthesis and release of PTH.
The increase in PTH favors bone turnover and resorption and stimulates the production of 1-α-hydroxylase, which increases and normalize serum calcium.
On the other hand , the increase in FGF23 and PTH favor urinary phosphate excretion, maintaining normal serum phosphate levels until stages 3–4 of CKD.
Despite the compensatory increases in PTH, but in CKD there is currently a hyporesponsiveness to PTH which limits its action.
And despite the fact that FGF23 and PTH have synergistic effects in relation to the renal excretion of phosphate, but they have opposite effects on calcitriol synthesis
the factors with greatest impact in the pathogenesis of CKD-MBD?what we should expect in CKD 5 would be a high prevalence of secondary hyperparathyroidism with high bone turnover, but the latter is not the most frequent findings within the CKD-MBD in the decades the more frequent pattern of bone lesions has changed from high to low bone turnover .
Could be due to: aging of the CKD ptient, the increase in the prevalence of diabetic nephropathy, the excess of calcium and vitamin D, and the aluminum load (less frequnt now),
Great explanation. Thanks Dr. Rola
the earliest events in pathogenesis of CKD-MBD
1-RELEASE OF FGF23 /KLOTHO >>as phosphaturic hormones and maintain serum po4 in normal value ,and inhibit alfa 1 hydroxylase so reduce 1,25(OH)2 D3
2- by loss of nephron mass and decrease klotho >>FGF23 lost his action and increase as amarker of cardiovascular morbidity and mortality (LVH )
3-hyperphosphatemia (dt loss of action of FGF23 and increase dietary intake )
4-decrease active vitamin D dt loss of 1 alfa hydroxylation from kidney
5- mild hypocalemia dt vitamin d deficiency and hyperphosphatemia
6-elevated hyperparathyroidism
===================
at the end we have
1-increase FGF23 and decrease klotho 2-increase serum phosphate 3- hypocalcemia 4-decrease active vitamin D 5-increased PTH
Good answer Dr. Emad
The factors with greatest impact in the pathogenesis of CKD-MBD are:
The excessive use of calcium and vitamin D receptor activators.
– the earliest events ;
-Reduced renal mass and GFR
-Decrease Klotho Increase FGF23 increases sclerostin
– factors with greatest impact in the pathogenesis of CKD-MBD;
Excessive use of calcium ,VDRAs, aging ,AL load ,immobility and comorbidities like DM.
Thanks Dr. Ahmed
the earliest event in pathogenesis in CKD -MBD
with progression of kidney function in CKD
the earliest event dysregulation of bone and mineral metabolism
hyper phosphoremia
CA
vit-D
PTH
but currently factor impact in pathogenesis of ckd-mbd
FGF-23 increased in early stage of ckd
and decrease of klotho
also another recent factor as wnt inhibitor ( sclerostin and dkk1 ) and actR11A
impact in renal bone disorders and calcification
Thanks Dr. Elsayed.
· The earliest events of pathogenesis of CKD-MBD are:
Increase in FGF23
Decrease of Klotho
Reduction of renal mass
These changes favor the low levels of calcitriol due to reduction of 1-α-hydroxylase in the kidney. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium. Hypocalcemia leads to stimulation of the synthesis and release of PTH.
· The factors with greatest impact in the pathogenesis of CKD-MBD are:
The excessive use of calcium and vitamin D receptor activators.
The pathophysiology of CKD-MBD is complex and involves feedback loops between the kidney, the parathyroid glands, the bone, the intestine, and the vasculature; to maintain calcium and phosphorus balance.
The earliest events in the pathophysiology of CKD-MBD as a consequence of decreased renal mass include:
Factors with a significant impact on the pathogenesis of CKD-MBD and pattern of bone lesions:
Great answer Dr. Amna
What are the earliest events?
-Reduced renal mass and GFR
-Decrease Klotho Increase FGF23 ( mostly the first thing to happen) increase sclerostin
-What are the factors with greatest impact in the pathogenesis of CKD-MBD?
Excessive use of: 1) calcium 2)(VDRAs)/ 4) aging 5) AL load 6)immobility 7) comorbidities like DM.
Good answer. Thanks Dr. Mahmoud.
the earliest events in the pathogenesis of CKD-MBD?with CKD, there is a gradual progressive decrease in the number of functioning nephrons leading to the following :
the factors with greatest impact in the pathogenesis of CKD-MBD?
Great clarification Dr. Ibrahim
As CKD develops, in earlier stages, with a decrease in renal mass, klotho decreases, and an increase in FGF-23 begins. At early stages, there is an attempt to decrease phosphorus, so FGF-23 and later PTH increase, maintaining normal P level. flowing the inactivation of 1 alfa hydroxylase leads to a decrease in 1,25(OH) Vit.D later leading to hypocalcemia, an inability to maintain normal P level
Thanks Dr. Mahmoud
The factors with greatest impact in the pathogenesis of CKD-MBD are:
The excessive use of calcium and vitamin D receptor activators.
Q1
In CKD diseases, the main alterations occur in Ca, phosphate, FGF23, klotho and the bit d hormonal system, including calcitriol and calcidiol, which lead to important changes in bone and vascular metabolism with very negative clinical consequences such as decreased bone mass and increased fragility, increased vascular calcifications. This process for the last six decades known as renal osteodystrophy. In 2006,a KDIGO consensus coined the new term CKD-MBD AND this is because it doesn’t confine to bone and laboratory finding alone but also other common complications.
CKD-MBD started early in CKD but became more florid in the late stages of CKD 4.5, and one of the factors that aggravate and increase the CKD-MBD is the use of excessive Ca and Vitamin D receptors activators, which can start the reduction in bone remodeling early.
It is currently accepted that an increase in FGF23, and decrease in KLOTHO, and a reduction of renal mass are the earliest events, these changes lead to a reduction in 1alpha hydroxylates which is the most natural activator of VDR., This in turn will reduce Ca absorption from the intestine, and this will lead to increase PTH production.
One of the crucial points in CKD-MBD, despite the synergistic effect of FGF23 and PTH in decreasing the phosphate level through the kidney, they have opposite effects on calcitriol synthesis, FGF23 inhibits1alpha hydroxylation, while PTH increases it.
Q2
As CKD progressed we expect to have secondary HPTH along with high bone turn over and this is not happened due to the following factors:
Ageing of ckd
DM
The excess use of Ca and Vit D, and because of this KDIGO guideline is to avoid hypercalcaemia in early CKD stage 2,3.
Thanks Dr. Rihab
The earliest events in the Pathogenesis of CKD-MBD:
– An increase in FGF23,
– A decrease in Klotho,
– A decrease in renal mass
– Increased vascular and valvular calcification.
The most significant changes occur in the calcium, phosphate, PTH, FGF23/Klotho, and vitamin D hormonal systems (calcidiol and calcitriol) , which cause significant alterations in bone and vascular metabolism with severe clinical effects such as decreased bone mass, increased fragility fractures, and increased vascular and valvular calcification.
Factors with greatest impact on in the pathogenesis of CKD-MBD:
– Excessive usage of calcium and vitamin D
– Aluminum load, which is becoming less common
– Rise in the incidence of diabetes as a cause of CKD
– Aging of the CKD population
Good answer Dr. Rania.
Q1
.
Q2
Thanks Dr. Ashraf. Good job.
1- icreased FGF-23 levels
2- decreased klotho levels and reduced renal mass
3- inactivation of 1-alpha hydroxylase in kidney
4- decreased active form of vit D
5- hyporesponsiveness to PTH action and secondary hyperparathyroidism
6- hypocalcemia due to decreased active vit D and decreased ca absorption from the intestine
7- phosphate retention later on
Thanks Dr. Mark.
Increase in FGF23
Decrease of Klotho
Reduction of renal mass
These changes favor the low levels of calcitriol due to reduction of 1-α-hydroxylase in the kidney. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium. Hypocalcemia leads to stimulation of the synthesis and release of PTH.
The excessive use of calcium and vitamin D receptor activators.
-What are the earliest events?
-What are the factors with greatest impact in the pathogenesis of CKD-MBD?
Good job Dr. Ben.
Thnxs prof
the earliest change in CKD-MBD is reduction of the functioning neprons and 2 opposite hormonal responses( increase FGF-23 AND decrease klotho), accumulating into decrease hydroxylase activity,decreasing calcitrol production, thereby decreasing intestinal calcium absorption, producing hypocalciumia which in turn stimulate PTH production. 2ry hyperparathyroidism and vit D deficiency lead CKD-MBD
Great Dr. Ahmed.
The factors with greatest impact in the pathogenesis of CKD-MBD are:
The excessive use of calcium and vitamin D receptor activators.
Increase FGF23, klotho deficiency both in parallel with reduction of renal mass are earliest changes in CKD-MBD which lead to decrease alfa hydroxylase in kidney then subsequently decrease calcitriol level which lead to decrease calcium absorption and hypocalcemia and secondary hyperparathyroidism.
the pathophysiology of secondary hyperparathyroidism:1- Plasma FGF23 increase with progression of CKD stages which occur before observed changes in the levels of phosphate and PTH, (FGF23) derived from osteocytes requires klotho (a transmembrane protein) to enable it to bind to the FGF receptor (FGFR) in classic target organs such as kidneys and parathyroid glands.2- Plasma FGF23 enhances phosphate excretion in the proximal renal tubule by decreasing the expression of luminal sodium-dependent phosphate transporters and may also decrease intestinal phosphate absorption by inhibiting NaPi cotransporter activity. 3- FGF23 reduces the synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D3] by down-regulating the activity of 1α-hydroxylase In the early stages of CKD, high levels of FGF23 attenuate hyperphosphatemia at the expense of 1,25(OH)2 vitamin D suppression, thus initiating the development of secondary hyperparathyroidism.4- The decrease in serum 1,25(OH)2D3 leads to decreased intestinal calcium absorption. The triad of calcium, calcitriol and hyperphosphatemia further enhances excessive PTH secretion. 5- This excess PTH leads to mobilization of calcium from the bone and osteitis fibrosa. Other consequences of progressive worsening of kidney function include hypo-responsiveness of the vitamin D receptor (VDR) on the parathyroid gland with further enhancement of production of PTH and reduced expression of the calcium-sensing receptor on the parathyroid gland leading to parathyroid gland hyperplasia. In some subsets of patients, the parathyroid gland undergoes hypertrophy and becomes autonomous
Thanks Dr. Ahmed.
The factors with greatest impact in the pathogenesis of CKD-MBD are:
The excessive use of calcium and vitamin D receptor activators.
Earliest events in the pathogenesis of CKD-MBD:
1-increase in FGF23
2-decrease of klotho expression
3-reduction of renal mass
These changes lead to reduction of 1-alpha hydroxylase, decrease in calcitriol, decrease intestinal calcium absorption,hypocalcemia and secondary hyperparathyroidism
Factors with greatest impact in the pathogenesis of CKD-MBD:
Excellent answer Dr. Alaa
The earliest Events in the Pathogenesis of CKD-MBD are:
These reduce 1-α-hydroxylase in the kidney resulting in low calcitriol and hypocalcemia which stimulate PTH release. PTH favors bone turnover
Factors with the greatest impact on the pathogenesis of CKD-MBD are:
Excellent. Thanks Dr. Mohammed.
Thanks Dr. Weam
Increase in FGF23
Decrease of Klotho
Reduction of renal mass
These changes favor the low levels of calcitriol due to reduction of 1-α-hydroxylase in the kidney. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium. Hypocalcemia leads to stimulation of the synthesis and release of PTH.
The excessive use of calcium and vitamin D receptor activators.
-The earliest event in CKD are:
1. Increased FGF23
2. Decrease in klotho
3. Decrease in renal mass
FGF inhibit 1alpha hydroxylase, so we will have a low 1,25 OH Vit D level too. Low vitamin D will cause hypocalcemia.
The hypocalcemia will stimulate or lead to increased PTH later on. (High phosphat will lead also to increased PTH)
The effects of phosphat on PTH is also carried out through it action on caSR.
-the factors with greatest impact in the pathogenesis of CKD-MBD are:
1.increased age 2. DM 3. Excess of calcium and vitamin D use 4. Aluminum load
Nice answer. Thanks Dr. Nour
The earliest event in ckd – MBD are increase in FGF23, decrease in klotho and decrease in renal mass. These will lead to decrease 1 alfa hydrxylase then decrease calcitriol, calcium and at the beginning increase phosphote in urine then subsequently increase S. Phosphorous.
The factors with the greatest impact are *excessive use of calcium and vitamin D receptors activators
*inadequate increase in S. Calcium
*aging of ckd population
*increase in prevalence of DM
*aluminum load (less frequent now)
Good job Dr. Israa
The earliest events in the Pathogenesis of CKD-MBD:
This is followed by altreation in Calcium, phosphate, PTH, and vitamin D hormonal system, (calidol and calcitriol), which lead to an important changes in bone and vascular metabolism with subsequent negative clinical sequelle:
Factors with greatest impact on in the pathogenesis of CKD-MBD:
All can lead to excessive impression of PTH and the reduction of bone remodeling.
Great. Thanks Dr. Kamal